title: Hypericum hircinum L. components as new single-molecule inhibitors of both HIV-1 reverse transcriptase-associated DNA polymerase and ribonuclease H activities.
abstract: Among HIV-1 reverse transcriptase (RT)-associated functions, DNA polymerase and Ribonuclease H (RNase H) are both essential for HIV replication and excellent targets for drug development. While all RT inhibitors approved for therapy target the DNA polymerase activity, there is the pressing need for new RT inhibitors possibly targeting the RNase H function. In the last 20 years, many natural substances have shown antiviral activity against HIV-1, but only a few against the RNase H function. In this study, we have tested the ethanolic extracts obtained by the Hypericum hircinum L. (Hypericaceae) growing in Sardinia (Italy) on the HIV-1 RT-associated RNase H function and found that they have inhibitory effects. Active extracts were fractionated up to obtain the main components that have been isolated, tested, and identified to be betulinic acid, shikimic acid, chlorogenic acid, quercetin, 5,7,3',5'-tetrahydroxyflavanone, and 5,7,3',5'-tetrahydroxyflavanone 7-O-glucoside. Betulinic acid and 5,7,3',5'-tetrahydroxyflavanone 7-O-glucoside were active on both RT-associated activities, and betulinic acid was also active on HIV-1 mutant RTs resistant to efavirenz. Overall, our results suggest that some of these compounds inhibit the HIV-1 RT binding to an allosteric site previously described for other natural compounds and are potential leads for further drug development of a single molecules having dual inhibitory activity.
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sanna
authors.forename: Claudia
authors.initials: C
authors.lastname: Del Vecchio
authors.forename: Valeria
authors.initials: V
authors.lastname: Cannas
authors.forename: Alessandro
authors.initials: A
authors.lastname: Venditti
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.forename: Armandodoriano
authors.initials: A
authors.lastname: Bianco
authors.forename: Anna M
authors.initials: AM
authors.lastname: Serrilli
authors.forename: Laura
authors.initials: L
authors.lastname: Guarcini
authors.forename: Cristina
authors.initials: C
authors.lastname: Parolin
authors.forename: Mauro
authors.initials: M
authors.lastname: Ballero
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005591:Chemical Fractionation; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007558:Italy; D009682:Magnetic Resonance Spectroscopy; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010936:Plant Extracts; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus
keywords: HIV; RNase H; RT; betulinic acid; dual inhibitors